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Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer
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Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer
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Journal Article
Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer
2017
Overview
Key Points
Molecular alterations fostering the progression of colorectal cancers are acquired early in the carcinogenesis process, and there is inter-connectivity among genomic drivers (gene mutations and chromosomal instability), transcriptomic subtypes (microsatellite instability immune, canonical, metabolic or mesenchymal) and immune signatures (highly immunogenic, poorly immunogenic or inflamed and immune tolerant).
Primary and metastatic samples display major similarities at the genomic level: novel gene alterations are usually related to chemotherapy or targeted therapy pressure. More studies on inter-metastatic spatial heterogeneity, molecular shifts at the transcriptomic level and changes in microenvironment markers are needed.
Until recently, the evolution of biomarkers for targeted therapies in colorectal cancer has been restrictive, with the identification of multiple negative predictive factors determining the response to epidermal growth factor receptor (EGFR) monoclonal antibodies. At progression to these agents, there is convergent reactivation of MAPK pathway
Emerging positive predictive markers for targeted therapies include infrequent genomic events, such as
BRAF
V600E
mutations,
ERBB2
amplifications, anaplastic lymphoma kinase (
ALK
) and neurotrophic receptor tyrosine kinase (
NTRK
) fusions and alterations in upstream nodes of the WNT pathway, such as ring finger protein 43 (
RNF43
), zinc and ring finger 3 (
ZNRF3
) and R-spondin (
RSPO
) genes. For immune checkpoint inhibitors, promising biomarkers include microsatellite instability and DNA polymerase-ε (
POLE
) mutations
Biomarker–drug co-development has evolved to accommodate a 'multi-molecular, multi-drug' perspective of precision medicine. Novel contexts of vulnerability are likely to be identified, leading to drug-repurposing strategies and combination therapies to halt tumour evolution and tackle minimal residual disease.
In this Review, Dienstmann
et al
. analyse the complex nature of colorectal cancer and the different subtypes in which this disease can be classified, advocating for a 'multi-molecular' perspective for the development of therapies to treat it.
Critical driver genomic events in colorectal cancer have been shown to affect the response to targeted agents that were initially developed under the 'one gene, one drug' paradigm of precision medicine. Our current knowledge of the complexity of the cancer genome, clonal evolution patterns under treatment pressure and pharmacodynamic effects of target inhibition support the transition from a one gene, one drug approach to a 'multi-gene, multi-drug' model when making therapeutic decisions. Better characterization of the transcriptomic subtypes of colorectal cancer, encompassing tumour, stromal and immune components, has revealed convergent pathway dependencies that mandate a 'multi-molecular' perspective for the development of therapies to treat this disease.
Publisher
Nature Publishing Group UK,Nature Publishing Group
